The medullary raphe nuclei, wherein serotonin (5-HT) coexists with substance P (SP) and thyrotropin-releasing hormone (TRH), innervate lower motor neurons in the spinal cord ventral horn by means of the ventral raphe-spinal pathway. Destruction of the ventral raphe-spinal pathway is associated with deficient recovery of denervated muscle, indicating that it may exert a trophic effect upon lower motor neurons. To determine whether SP could be a trophic factor for lower motor neurons within the ventral raphe-spinal pathway, the effect of muscle denervation with botulinum toxin type A on SP-encoding beta-preprotachykinin mRNA in the rat medullary raphe was examined by in situ hybridization histochemistry. Silver grain density over hybridized medullary raphe neurons was increased by up to 11%, although the number of hybridized neurons did not change in denervated as compared to control rats. Increased SP gene expression in the medullary raphe in response to motor unit lesioning suggests that raphe-spinal SP may be trophic to lower motor neurons.